US4088646A - 5-Fluorouracil derivatives - Google Patents
5-Fluorouracil derivatives Download PDFInfo
- Publication number
- US4088646A US4088646A US05/651,370 US65137076A US4088646A US 4088646 A US4088646 A US 4088646A US 65137076 A US65137076 A US 65137076A US 4088646 A US4088646 A US 4088646A
- Authority
- US
- United States
- Prior art keywords
- fluorouracil
- acid
- benzoyl
- spectrum
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- -1 heneicosanyl Chemical group 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 101150108015 STR6 gene Proteins 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 230000001093 anti-cancer Effects 0.000 abstract description 7
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 229960002949 fluorouracil Drugs 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- SOLWGCGTQNTUDI-UHFFFAOYSA-N 1,3-dibenzoyl-5-fluoropyrimidine-2,4-dione Chemical compound O=C1N(C(=O)C=2C=CC=CC=2)C(=O)C(F)=CN1C(=O)C1=CC=CC=C1 SOLWGCGTQNTUDI-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OAPBZIITNDJWQW-UHFFFAOYSA-N 3-benzoyl-5-fluoro-1h-pyrimidine-2,4-dione Chemical compound O=C1C(F)=CNC(=O)N1C(=O)C1=CC=CC=C1 OAPBZIITNDJWQW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000002211 ultraviolet spectrum Methods 0.000 description 5
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- WVJVHUWVQNLPCR-UHFFFAOYSA-N octadecanoyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC WVJVHUWVQNLPCR-UHFFFAOYSA-N 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N pentadecanoic acid Chemical compound CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- OVGDAVVFKDPXIC-UHFFFAOYSA-N 1-acetyl-5-fluoropyrimidine-2,4-dione Chemical compound CC(=O)N1C=C(F)C(=O)NC1=O OVGDAVVFKDPXIC-UHFFFAOYSA-N 0.000 description 2
- RQNLYAYTZCUHLO-UHFFFAOYSA-N 1-benzoyl-5-fluoropyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(F)=CN1C(=O)C1=CC=CC=C1 RQNLYAYTZCUHLO-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- PMUWVZSKOIUUFO-UHFFFAOYSA-N 5-fluoro-1-heptadecanoylpyrimidine-2,4-dione Chemical compound CCCCCCCCCCCCCCCCC(=O)N1C=C(F)C(=O)NC1=O PMUWVZSKOIUUFO-UHFFFAOYSA-N 0.000 description 2
- HJAGLRPKKXNJRK-UHFFFAOYSA-N 5-fluoro-1-hexadecanoylpyrimidine-2,4-dione Chemical compound CCCCCCCCCCCCCCCC(=O)N1C=C(F)C(=O)NC1=O HJAGLRPKKXNJRK-UHFFFAOYSA-N 0.000 description 2
- SCTGOFNBLRSUKA-UHFFFAOYSA-N 5-fluoro-1-octadecanoylpyrimidine-2,4-dione Chemical compound CCCCCCCCCCCCCCCCCC(=O)N1C=C(F)C(=O)NC1=O SCTGOFNBLRSUKA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- CKDDRHZIAZRDBW-UHFFFAOYSA-N henicosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCC(O)=O CKDDRHZIAZRDBW-UHFFFAOYSA-N 0.000 description 2
- KEMQGTRYUADPNZ-UHFFFAOYSA-N heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)=O KEMQGTRYUADPNZ-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- ISYWECDDZWTKFF-UHFFFAOYSA-N nonadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(O)=O ISYWECDDZWTKFF-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- CNVZJPUDSLNTQU-SEYXRHQNSA-N petroselinic acid Chemical compound CCCCCCCCCCC\C=C/CCCCC(O)=O CNVZJPUDSLNTQU-SEYXRHQNSA-N 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 150000004992 toluidines Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XEZVDURJDFGERA-UHFFFAOYSA-N tricosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCC(O)=O XEZVDURJDFGERA-UHFFFAOYSA-N 0.000 description 2
- SZHOJFHSIKHZHA-UHFFFAOYSA-N tridecanoic acid Chemical compound CCCCCCCCCCCCC(O)=O SZHOJFHSIKHZHA-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BITHHVVYSMSWAG-KTKRTIGZSA-N (11Z)-icos-11-enoic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCC(O)=O BITHHVVYSMSWAG-KTKRTIGZSA-N 0.000 description 1
- XSXIVVZCUAHUJO-AVQMFFATSA-N (11e,14e)-icosa-11,14-dienoic acid Chemical compound CCCCC\C=C\C\C=C\CCCCCCCCCC(O)=O XSXIVVZCUAHUJO-AVQMFFATSA-N 0.000 description 1
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- CLWAXFZCVYJLLM-UHFFFAOYSA-N 1-chlorohexadecane Chemical compound CCCCCCCCCCCCCCCCCl CLWAXFZCVYJLLM-UHFFFAOYSA-N 0.000 description 1
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- FOYWCEUVVIHJKD-UHFFFAOYSA-N 2-methyl-5-(1h-pyrazol-5-yl)pyridine Chemical compound C1=NC(C)=CC=C1C1=CC=NN1 FOYWCEUVVIHJKD-UHFFFAOYSA-N 0.000 description 1
- WXBXVVIUZANZAU-UHFFFAOYSA-N 2E-decenoic acid Natural products CCCCCCCC=CC(O)=O WXBXVVIUZANZAU-UHFFFAOYSA-N 0.000 description 1
- NRMBVSOZTBXMAE-UHFFFAOYSA-N 3-benzoyl-5-fluoro-1-octadecanoylpyrimidine-2,4-dione Chemical compound O=C1N(C(=O)CCCCCCCCCCCCCCCCC)C=C(F)C(=O)N1C(=O)C1=CC=CC=C1 NRMBVSOZTBXMAE-UHFFFAOYSA-N 0.000 description 1
- JFKUBRAOUZEZSL-UHFFFAOYSA-N 4-butylbenzoic acid Chemical compound CCCCC1=CC=C(C(O)=O)C=C1 JFKUBRAOUZEZSL-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- ROFDHRBMFQYNKJ-UHFFFAOYSA-N 5-fluoro-1,3-bis(4-nitrobenzoyl)pyrimidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)N1C(=O)N(C(=O)C=2C=CC(=CC=2)[N+]([O-])=O)C(=O)C(F)=C1 ROFDHRBMFQYNKJ-UHFFFAOYSA-N 0.000 description 1
- XUOHLCISGFTYQZ-UHFFFAOYSA-N 5-fluoro-3-(4-nitrobenzoyl)-1h-pyrimidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)N1C(=O)C(F)=CNC1=O XUOHLCISGFTYQZ-UHFFFAOYSA-N 0.000 description 1
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- YWWVWXASSLXJHU-UHFFFAOYSA-N 9E-tetradecenoic acid Natural products CCCCC=CCCCCCCCC(O)=O YWWVWXASSLXJHU-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- GZZPOFFXKUVNSW-UHFFFAOYSA-N Dodecenoic acid Natural products OC(=O)CCCCCCCCCC=C GZZPOFFXKUVNSW-UHFFFAOYSA-N 0.000 description 1
- 235000021297 Eicosadienoic acid Nutrition 0.000 description 1
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 235000021353 Lignoceric acid Nutrition 0.000 description 1
- CQXMAMUUWHYSIY-UHFFFAOYSA-N Lignoceric acid Natural products CCCCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 CQXMAMUUWHYSIY-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
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- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FARYTWBWLZAXNK-WAYWQWQTSA-N ethyl (z)-3-(methylamino)but-2-enoate Chemical compound CCOC(=O)\C=C(\C)NC FARYTWBWLZAXNK-WAYWQWQTSA-N 0.000 description 1
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- KPELOSDOWOWZSG-UHFFFAOYSA-N heptadecanoyl heptadecanoate Chemical compound CCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCC KPELOSDOWOWZSG-UHFFFAOYSA-N 0.000 description 1
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- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- NNNVXFKZMRGJPM-KHPPLWFESA-N sapienic acid Chemical compound CCCCCCCCC\C=C/CCCCC(O)=O NNNVXFKZMRGJPM-KHPPLWFESA-N 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- IBYFOBGPNPINBU-UHFFFAOYSA-N tetradecenoic acid Natural products CCCCCCCCCCCC=CC(O)=O IBYFOBGPNPINBU-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- WXBXVVIUZANZAU-CMDGGOBGSA-N trans-2-decenoic acid Chemical compound CCCCCCC\C=C\C(O)=O WXBXVVIUZANZAU-CMDGGOBGSA-N 0.000 description 1
- IBYFOBGPNPINBU-OUKQBFOZSA-N trans-2-tetradecenoic acid Chemical compound CCCCCCCCCCC\C=C\C(O)=O IBYFOBGPNPINBU-OUKQBFOZSA-N 0.000 description 1
- AQWHMKSIVLSRNY-UHFFFAOYSA-N trans-Octadec-5-ensaeure Natural products CCCCCCCCCCCCC=CCCCC(O)=O AQWHMKSIVLSRNY-UHFFFAOYSA-N 0.000 description 1
- LKOVPWSSZFDYPG-WUKNDPDISA-N trans-octadec-2-enoic acid Chemical compound CCCCCCCCCCCCCCC\C=C\C(O)=O LKOVPWSSZFDYPG-WUKNDPDISA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
Definitions
- This invention relates to novel 5-fluorouracil derivatives useful as an anti-cancer or anti-tumor agent. More particularly, this invention relates to 5-fluorouracil derivatives represented by the formulae: ##STR2## wherein R 1 represents an aryl group having 6 to 10 carbon atoms and R 2 represents an alkyl or alkenyl group having 9 to 23 carbon atoms.
- 5-Fluorouracil is a compound which inhibits the formation of nucleic acids in a living body by its metabolic antagonism, and, therefore, is useful as an anti-tumor agent.
- 5-Fluorouracil has been employed in the form of 1-N-substituted derivatives thereof, for example, the 1-N-tetrahydrofuranyl derivatives.
- the tetrahydrofuranyl group at the 1-N-substituent is a specific group and the industrial production thereof involves high costs.
- Other 1-N-substituted derivatives which have hitherto been proposed include 1-N-acetyl-5-fluorouracil (see U.S. Pat. No.
- 1-N-benzoyl-5-fluorouracil see Gann, 65, 463, 1974
- 1,3-di-N-benzoyl-5-fluorouracil see West German Patent 2,455,423.
- 1-N-acetyl-5-fluorouracil is highly toxic
- 1-N-benzoyl-5-fluorouracil cannot be synthesized on a reproducible basis
- 1,3-di-N-benzoyl-5-fluorouracil does not show reproducible activity.
- the inventors conducted extensive investigations in order to develop novel compounds which can be produced on an industrial scale without the above described disadvantages associated with conventional 1-N-substituted-5-fluorouracils. As a result, the inventors found that uracil derivatives which have superior physiological activity to that of 1-N-tetrahydrofuranyl-5-fluorouracil and which are also of low toxicity can be obtained by using a higher aliphatic acyl group as a 1-N-substituent or an aromatic acyl group as a 3-N-substituent, thereby reaching the present invention.
- the present invention therefore, provides compounds represented by the formulae: ##STR3## wherein R 1 represents an aryl group having 6 to 10 carbon atoms and R 2 represents an alkyl or alkenyl group having 9 to 23 carbon atoms, which possess superior physiological activity over that of 1-N-tetrahydrofuranyl-5-fluorouracil.
- FIGS. 1 to 6 show infrared absorption spectra of compounds according to the present invention.
- aryl group having 6 to 10 carbon atoms used for R 1 designates groups such as a phenyl, p-nitrophenyl, p-tolyl, p-methoxyphenyl and a p-n-butylphenyl group, preferably a phenyl group.
- alkyl group used to define R 2 designates a straight or branched chain alkyl group having 9 to 23 carbon atoms such as a nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosanyl, heneicosanyl, docosanyl and a tricosanyl group, preferably a pentadecyl, hexadecyl or heptadecyl group.
- alkenyl group used to define R 2 designates a straight or branched chain alkenyl group having 9 to 23 carbon atoms such as a 7-nonenyl, 7-pentadecenyl, 9-heptadecenyl and a 9-tricosenyl group.
- the 5-fluorouracil derivatives according to the present invention can be prepared by reacting 5-fluorouracil with an aromatic carboxylic acid halide represented by formula (III):
- R 1 is as defined above and X represents a halogen atom such as a fluorine, chlorine, bromine or iodine atom.
- X represents a halogen atom such as a fluorine, chlorine, bromine or iodine atom.
- the compounds of this invention can be prepared by reacting 5-fluorouracil with a reactive functional derivative of an organic acid represented by formula (IV):
- the acylating agent having formula (III) which can be used in this invention includes chlorides and bromides of an aromatic carboxylic acid such as benzoic acid, toluic acid, p-nitrobenzoic acid, anisic acid, p-n-butylbenzoic acid and the like.
- the acylating agent of formula (III) is used in an amount of about 1 to about 2 molar times the amount of 5-fluorouracil.
- the reaction between 5-fluorouracil and the aromatic carboxylic acid halide of formula (III) is advantageously, but not mandatorily, carried out in a solvent in the presence of a base.
- Suitable solvents are non-polar solvents such as dioxane, benzene and the like.
- Preferred bases include organic bases such as pyridine, picoline, toluidine, triethylamine, dimethylaniline and the like. It is preferred to use these bases in an amount of from about 1 to about 20 molar equivalents with respect to the acylating agent employed, and the solvent in an amount of from about 1 to about 5 times the volume of the base used.
- the above reaction is suitably carried out under 1 to 5 atmospheres pressure at a temperature from about 50 to about 150° C for a period of from about 0.5 to about 2 hours.
- any unreacted reactants remaining in the reaction mixture are removed therefrom, whereafter the mixture can be purified, if necessary, by washing followed by either recrystallization from a solvent such as ethanol, isopropanol, benzene, ethyl acetate, hexane or the like, or chromatography using a silica gel column.
- the organic acid represented by formula (IV) which can be used in this invention to introduce a substituent to the 1-N-position of 5-fluorouracil includes, for example, saturated aliphatic acids such as capric acid, n-undecanoic acid, lauric acid, n-tridecanoic acid, myristic acid, n-pentadecanoic acid, palmitic acid, margaric acid, stearic acid, n-nonadecanoic acid, arachidic acid, n-heneicosanoic acid, behenic acid, n-tricosanoic acid, lignoceric acid and the like, and unsaturated aliphatic acids such as decenoic acid, undecenoic acid, dodecenoic acid, tetradecenoic acid, hexadecenoic acid, octadecenoic acid, oleic acid, petroselinic acid, linolic acid, eicosenoic acid,
- organic acids can be used in the form of a reactive functional derivative thereof, for example, in the form of an acid ester, an acid anhydride or an acid halide. It is preferable to use the functional derivative of the above described organic acid of formula (IV) in an amount of from about 1.5 to about 5 molar equivalents relative to 5-fluorouracil.
- bases are organic bases such as pyridine, picoline, toluidine, triethylamine, dimethylaniline and the like. Such a base is generally used in an amount of from about 2 to about 20 molar equivalents based on the acid anhydride or acid halide used.
- a solvent non-polar solvents such as dioxane, benzene and the like are most suitable. The solvent is suitably used in an amount of from about 1 to about 5 times the volume of the above described base.
- the reaction between 5-fluorouracil and the reactive functional derivative of the compound of formula (IV) can generally be carried out under 1 to 5 atmospheres pressure at a temperature ranging from about 50° to about 150° C for a period of from about 0.5 to about 2 hours.
- the reaction mixture can be washed with hexane, benzene, acetone or a like solvent to remove most of the organic acid and unreacted reactants, if necessary, whereafter the residue is purified by recrystallization from an appropriate solvent, such as benzene, toluene, ethyl acetate, diethyl ether, hexane and the like.
- the structure of the compounds according to the present invention as illustrated by chemical formulae (I) or (II) can be determined by the chemical shift of the nuclear magnetic resonance spectrum of the 6-position proton (H 6 ). That is, the 5-fluorouracil is capable of being acylated either at the 1-N-position or the 3-N-position.
- the chemical shift of H 6 of 5-fluorouracil in pyridine-d 5 is ⁇ 7.74 ppm, and when the 5-fluorouracil is acylated, the H 6 shifts to the lower magnetic field.
- the compounds obtained according to the present invention are useful as an anti-cancer or anti-tumor agent.
- UV Absorption Spectrum UV: ⁇ max 254 m ⁇ (methanol).
- the infrared absorption spectrum (IR) of the above product is shown in FIG. 1.
- the anti-cancer activity of the compounds according to this invention against L1210 was compared with that of a commercially available anti-cancer agent, 1-N-tetrahydrofuranyl-5-fluorouracil.
- a commercially available anti-cancer agent 1-N-tetrahydrofuranyl-5-fluorouracil.
- the compounds of this invention exhibited superior anti-cancer effects against L1210 as compared to those of 1-N-tetrahydrofuranyl-5-fluorouracil as shown in the following Biological Experimentation Example.
- mice 1 ⁇ 10 5 cells of L1210 were intraperitionally transplanted to mice (CDF 1 , 10 mice per group). 24 hours after the transplant, the test compound as indicated in the Table below (10 to 100 mg of the test compound was suspended in 1 ml of a physiological saline solution and 0.05 ml of Tween-80 (trade name of a nonionic surface active agent, manufactured by Atlas Powder Co., U.S.A.) was added thereto) was administered to each mouse at a single dose level of 10 to 100 mg/kg body weight per day for a period of 5 days. As a control, a mixture of Tween-80 and a physiological saline solution containing no test compound was administered.
- Tween-80 trade name of a nonionic surface active agent, manufactured by Atlas Powder Co., U.S.A.
- the anti-cancer effects of the test compounds are shown in the Table below in terms of the percentage of the average survival days in test groups (T) to the average survival days in a control group (C) (T/C %). Therefore, a T/C % less than 100% indicates the test compound was toxic whereas a T/C % higher than 100% indicates that the compound possessed an anti-cancer effect.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP50009469A JPS5186479A (en) | 1975-01-22 | 1975-01-22 | 55 furuororashirujudotainoseizohoho |
| JA50-9469 | 1975-01-22 | ||
| JA50-9470 | 1975-01-22 | ||
| JP50009470A JPS6024102B2 (ja) | 1975-01-22 | 1975-01-22 | ５−フルオロウラシル誘導体の製法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4088646A true US4088646A (en) | 1978-05-09 |
Family
ID=26344210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/651,370 Expired - Lifetime US4088646A (en) | 1975-01-22 | 1976-01-22 | 5-Fluorouracil derivatives |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US4088646A (enExample) |
| DE (1) | DE2602175B2 (enExample) |
| FR (1) | FR2298332A1 (enExample) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4190656A (en) * | 1977-09-22 | 1980-02-26 | Takeda Chemical Industries, Ltd. | Uracil derivatives and production thereof |
| US4196202A (en) * | 1977-12-20 | 1980-04-01 | Taiji Okada | Carcinostatic composition containing 3-N-o-toluyl-5-fluorouracil producing the same |
| US4329460A (en) * | 1976-03-31 | 1982-05-11 | Takeda Chemical Industries, Ltd. | Uracil derivatives and production thereof |
| US4349552A (en) * | 1978-10-30 | 1982-09-14 | Fujisawa Pharmaceutical Company, Ltd. | 5-Fluorouracil derivatives, and their pharmaceutical compositions |
| US6107499A (en) * | 1988-02-26 | 2000-08-22 | Neuromedica, Inc. | Dopamine analog amide |
| US20020177609A1 (en) * | 2001-03-23 | 2002-11-28 | Swindell Charles S. | Fatty alcohol drug conjugates |
| US20030065023A1 (en) * | 2001-03-23 | 2003-04-03 | Swindell Charles S. | Fatty amine drug conjugates |
| US6576636B2 (en) | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
| US6602902B2 (en) | 1996-05-22 | 2003-08-05 | Protarga, Inc. | Dha-pharmaceutical agent conjugates to improve tissue selectivity |
| US20030236111A1 (en) * | 2002-06-21 | 2003-12-25 | Namco Ltd. | Game performing method, storage medium, game apparatus, data signal and program |
| US7235583B1 (en) | 1999-03-09 | 2007-06-26 | Luitpold Pharmaceuticals, Inc., | Fatty acid-anticancer conjugates and uses thereof |
| WO2017123823A1 (en) * | 2016-01-12 | 2017-07-20 | Bioelectron Technology Corporation | Alkyl-, acyl-, urea-, and aza-uracil sulfide:quinone oxidoreductase inhibitors |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2648998C1 (ru) * | 2017-03-29 | 2018-03-29 | Александр Александрович Озеров | Способ получения монозамещенных производных урацила |
| RU2643520C1 (ru) * | 2017-04-11 | 2018-02-02 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный медицинский университет" Министерства здравоохранения Российской Федерации ФГБОУ ВО ВолгГМУ МЗ РФ | 1,3-Бис(4-метоксибензоил)пиримидин-2,4(1Н,3Н)-дион, обладающий разрывающей поперечные сшивки гликированных белков активностью |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2949451A (en) * | 1959-04-21 | 1960-08-16 | Hoffmann La Roche | Preparation of thymidine and deoxyfluorouridine, and intermediates therefor |
| US3971784A (en) * | 1973-11-28 | 1976-07-27 | Mitsui Pharmaceuticals, Incorporated | 5-Fluorouracil derivatives |
-
1976
- 1976-01-21 DE DE2602175A patent/DE2602175B2/de active Granted
- 1976-01-21 FR FR7601584A patent/FR2298332A1/fr active Granted
- 1976-01-22 US US05/651,370 patent/US4088646A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2949451A (en) * | 1959-04-21 | 1960-08-16 | Hoffmann La Roche | Preparation of thymidine and deoxyfluorouridine, and intermediates therefor |
| US3971784A (en) * | 1973-11-28 | 1976-07-27 | Mitsui Pharmaceuticals, Incorporated | 5-Fluorouracil derivatives |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4329460A (en) * | 1976-03-31 | 1982-05-11 | Takeda Chemical Industries, Ltd. | Uracil derivatives and production thereof |
| US4190656A (en) * | 1977-09-22 | 1980-02-26 | Takeda Chemical Industries, Ltd. | Uracil derivatives and production thereof |
| US4196202A (en) * | 1977-12-20 | 1980-04-01 | Taiji Okada | Carcinostatic composition containing 3-N-o-toluyl-5-fluorouracil producing the same |
| US4349552A (en) * | 1978-10-30 | 1982-09-14 | Fujisawa Pharmaceutical Company, Ltd. | 5-Fluorouracil derivatives, and their pharmaceutical compositions |
| US6107499A (en) * | 1988-02-26 | 2000-08-22 | Neuromedica, Inc. | Dopamine analog amide |
| US6602902B2 (en) | 1996-05-22 | 2003-08-05 | Protarga, Inc. | Dha-pharmaceutical agent conjugates to improve tissue selectivity |
| US6576636B2 (en) | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
| US8314077B2 (en) * | 1996-05-22 | 2012-11-20 | Luitpold Pharmaceuticals, Inc. | Fatty acid-pharmaceutical agent conjugates |
| US20040106589A1 (en) * | 1996-05-22 | 2004-06-03 | Protarga Pharmaceuticals, Inc. | Fatty acid-pharmaceutical agent conjugates |
| US20040180949A1 (en) * | 1996-05-22 | 2004-09-16 | Protarga, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
| US7199151B2 (en) | 1996-05-22 | 2007-04-03 | Luitpold Pharmaceuticals, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
| US7235583B1 (en) | 1999-03-09 | 2007-06-26 | Luitpold Pharmaceuticals, Inc., | Fatty acid-anticancer conjugates and uses thereof |
| US20080125380A1 (en) * | 1999-03-09 | 2008-05-29 | Luitpold Pharmaceuticals, Inc. | Fatty acid-anticancer conjugates and uses thereof |
| US7816398B2 (en) | 2001-03-23 | 2010-10-19 | Luitpold Pharmaceuticals, Inc. | Fatty alcohol drug conjugates |
| US20030065023A1 (en) * | 2001-03-23 | 2003-04-03 | Swindell Charles S. | Fatty amine drug conjugates |
| US20020177609A1 (en) * | 2001-03-23 | 2002-11-28 | Swindell Charles S. | Fatty alcohol drug conjugates |
| US8552054B2 (en) | 2001-03-23 | 2013-10-08 | Luitpold Pharmaceuticals, Inc. | Fatty amine drug conjugates |
| US20030236111A1 (en) * | 2002-06-21 | 2003-12-25 | Namco Ltd. | Game performing method, storage medium, game apparatus, data signal and program |
| WO2017123823A1 (en) * | 2016-01-12 | 2017-07-20 | Bioelectron Technology Corporation | Alkyl-, acyl-, urea-, and aza-uracil sulfide:quinone oxidoreductase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2602175C3 (enExample) | 1979-01-11 |
| FR2298332B1 (enExample) | 1978-12-08 |
| DE2602175A1 (de) | 1976-07-29 |
| FR2298332A1 (fr) | 1976-08-20 |
| DE2602175B2 (de) | 1978-05-03 |
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